How Stress Controls the Inflammatory Cytokine Response

• Applicant: Professor Dr. Fred Schaper
• Co-Applicant: Professor Dr. Raymond Kaempfer
• Subject Area: Immunology ; Biochemistry
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 255537323

We examine the novel concept that the integrated cellular stress response plays a critical role in regulating inflammatory cytokine gene expression. Specifically, we aim to study how stress regulates the genes encoding tumor necrosis factor (TNF-alpha) and suppressor of cytokine signaling 3 (SOCS3), a broad negative regulator of inflammatory signaling. Jointly, we will investigate how this regulation is affected by the inflammatory cytokine IL-6, a major mediator of the acute-phase response, and by immunosuppressive glucocorticoids. The work is based on our discovery that multiple inflammatory cytokine genes contain potent intragenic RNA activators of PKR. Phosphorylation of eIF2-alpha by kinases, including the RNA-activated kinase, PKR, represses translation and is essential for mounting the integrated cellular stress response. IFN-gamma mRNA attenuates its own translation by locally activating PKR through a 5-proximal RNA structure. Efficient splicing of TNF-alpha mRNA requires a short 3-UTR element that activates PKR; activation of PKR induces eIF2-alpha phosphorylation strictly needed for splicing of this mRNA, revealing a novel, positive role for eIF2-alpha phosphorylation in mRNA splicing. SOCS3 is regulated by stress signaling via PKR and eIF2-alpha phosphorylation. SOCS3 protein is very short-lived, however, a more stable and more potent N-terminally truncated isoform, delta N-SOCS3, is induced strongly by PKR and by conditions that promote eIF2-alpha phosphorylation. We showed recently that glucocorticoids increase IL-6-dependent gene induction by inhibiting expression of SOCS3 protein while not affecting SOCS3 protein stability or level and stability of SOCS3 mRNA, suggestive of translational repression. We ask here whether the activation of PKR needed for stable delta N-SOCS3 synthesis is achieved through an intragenic SOCS3 RNA activator of PKR and whether glucocorticoids influence control via PKR and phosphorylation of eIF2-alpha.Activation of PKR and phosphorylation of eIF2-alpha control SOCS3 and TNF-alpha gene expression and both SOCS3 and TNF-alpha are regulated by IL-6 and glucocorticoids, creating a solid basis for this joint research. Findings emanating from this joint basic biological research focused on the mechanisms of stress signaling will impact on basic understanding of inflammatory processes essential for protective immunity and at the heart of many diseases.

• DFG Programme: Research Grants
• International Connection: Israel